Diversity of Secondary Structure in Catalytic Peptides with β-Turn-Biased Sequences

Abstract

X-ray crystallography has been applied to the structural analysis of a series of tetrapeptides that were previously assessed for catalytic activity in an atroposelective bromination reaction. Common to the series is a central Pro-Xaa sequence, where Pro is either l- or d-proline, which was chosen to favor nucleation of canonical β-turn secondary structures. Crystallographic analysis of 35 different peptide sequences revealed a range of conformational states. The observed differences appear not only in cases where the Pro-Xaa loop-region is altered, but also when seemingly subtle alterations to the flanking residues are introduced. In many instances, distinct conformers of the same sequence were observed, either as symmetry-independent molecules within the same unit cell or as polymorphs. Computational studies using DFT provided additional insight into the analysis of solid-state structural features. Select X-ray crystal structures were compared to the corresponding solution structures derived from measured proton chemical shifts, 3J-values, and 1H–1H-NOESY contacts. These findings imply that the conformational space available to simple peptide-based catalysts is more diverse than precedent might suggest. The direct observation of multiple ground state conformations for peptides of this family, as well as the dynamic processes associated with conformational equilibria, underscore not only the challenge of designing peptide-based catalysts, but also the difficulty in predicting their accessible transition states. These findings implicate the advantages of low-barrier interconversions between conformations of peptide-based catalysts for multistep, enantioselective reactions.

Parameterization and Analysis of Peptide-Based Catalysts for the Atroposelective Bromination of 3-Arylquinazolin-4(3H)-ones

“…6 For instance, type I′ and II′ β-turns, differing mainly by the orientation of the loop amide region (blue boxes, Figure 1b), 7 have been observed in the solid and solution states for several variations of 3 . 8 Ultimately, methods to simultaneously interrogate the flexibility and dynamics of these catalysts will facilitate an understanding of the enantioselectivity imparted in a given reaction and provide additional opportunities to predict new peptide catalyst performance.…”

“…10 Furthermore, a linear correlation between the crystallographic main-chain angle (τ) of the i +2 position (τ( i +2)) and enantioselectivity has been identified, although τ( i +2) exhibits clustering at 111° and 117°. 8,12 These experimental results suggested that initial modeling strategies should be directed at understanding how changes in the i +2 residue affect catalysis. Thus, a homologous series of peptides varying only at i +2 were synthesized and used as catalysts in the atroposelective bromination reaction to probe the effects of this residue on enantioselectivity (Figure 2).…”

“…This is in part due to the greater structural flexibility in the solid state observed at the i +3 position. 8 Additionally, incorporating the i +3 residue into the truncated i +2 model system would require the inclusion of the Dmaa residue to maintain the second hydrogen bond between N–H i and C=O i +3 that defines a β-hairpin conformation, thus increasing the computational effort needed to acquire descriptors even further. 21 Ultimately, as the catalytic moiety and D-proline are conserved for each of the tetrapeptides, we calculated the corresponding i +3 amino esters and amides to further account for the observed end-cap differences (Figure 1b).…”

Enantioselective Intermolecular C–O Bond Formation in the Desymmetrization of Diarylmethines Employing a Guanidinylated Peptide-Based Catalyst

“…This result is particularly interesting given that heterochirality between a defined secondary structures which in turn can affect catalysis. 14,15 This result is perhaps more striking when compared with L11 , which demonstrates the importance of the i residue’s stereo-configuration. Varying this stereocenter reversed enantioselectivity relative to epimeric ligand L10 , in addition to a reduction in the absolute selectivity with an er value of 34:66 (Table 2, entry 11).…”

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

“…43–45 As shown in Figure 4B, this C=O i to NH i+3 intramolecular hydrogen bond (H-bond) can stabilize the secondary structure of the peptide and provide a relatively consistent structure for catalysis. 46 This approach was also explored in reactions analogous to those catalyzed by kinases, culminating in the realization of peptide-catalyzed desymmetrizations of inositol derivatives (Figure 4C). 47–51 Here, two distinct peptide scaffolds are utilized to access different phosphorylated derivatives of 8 .…”